Project Summary/Abstract Obesity is a global epidemic; nearly 60% of women of reproductive age are considered overweight or obese in the U.S., and this percentage is continuously rising. The prevalence of childhood obesity is increasing at alarming rates, and children born from obese mothers have higher risks of developing diabetes, metabolic syndrome, and cardiovascular diseases. Compelling evidence from various species indicates that maternal obesity negatively influences the metabolic health of offspring and impacts various systems; however, there is a limited study investigating cardiac dysfunction of offspring born from obese mothers. Cardiomyopathy associated with mitochondrial disease occurs in 20-40% of children, and mitochondrial dysfunction is more prevalent in obese children than normal weight children. Unfortunately, the cellular and molecular mechanisms remain poorly understood. The long-term goal of this study is to determine the lifelong effects and mechanisms of an underlying abnormal maternal metabolic environment on cardiometabolic diseases in offspring and provide evidence for therapeutic strategy for preventing childhood obesity through maternal exercise. We have recently established pre-pregnancy and gestational obesity model in female mice in which the male offspring developed glucose intolerance and insulin resistance to a greater extent than female offspring. To address sex as a biological variable, both male and female offspring will be used to: 1) evaluate in vivo and in vitro contractile properties of the heart in response to maternal obesity with and without exercise; 2) determine morphological/structural alterations and gene expression of the heart born from obese mothers with and without exercise; and 3) determine oxidative stress and the mitochondrial function as the underlying mechanisms of maternal obesity and exercise on altered cardiometabolic health of offspring. Although the long-term beneficial effect of exercise on cardiac function is well documented in healthy normal weight population, to the best of our knowledge, our study is the first study to investigate the role of maternal exercise on cardiac function of offspring and the underlying mechanisms emphasizing on sex differences on mitochondrial function. The results of this proposed study will advance our knowledge of how maternal exercise modifies the cardiac structure, mitochondrial function, and overall heart function; and thus, could provide a new intervention for preventing heart disease associated with childhood obesity. Our proposal is well aligned with NIH?s mission to reduce the burden of chronic diseases.